The Kynurenine Pathway in Traumatic Brain Injury: Implications for Psychiatric Outcomes

Traumatic brain injury (TBI) is an established risk factor for the development of psychiatric disorders, especially depression and anxiety. However, the mechanistic pathways underlying this risk remain unclear, limiting treatment options and hindering the identification of clinically useful biomarkers. One salient pathophysiological process implicated in both primary psychiatric disorders and TBI is inflammation. An important consequence of inflammation is the increased breakdown of tryptophan to kynurenine and, subsequently, the metabolism of kynurenine into several neuroactive metabolites, including the neurotoxic NMDA receptor agonist quinolinic acid and the neuroprotective NMDA receptor antagonist kynurenic acid. Here, we review studies of the kynurenine pathway (KP) in TBI and examine their potential clinical implications. The weight of the literature suggests that there is increased production of neurotoxic kynurenines such as quinolinic acid in TBI of all severities and that elevated quinolinic acid concentrations in both the cerebrospinal fluid and blood are a negative prognostic indicator, being associated with death, magnetic resonance imaging abnormalities, increased depressive and anxiety symptoms, and prolonged recovery. We hypothesize that an imbalance in KP metabolism is also one molecular pathway through which the TBI-induced neurometabolic cascade may predispose to the development of psychiatric sequelae. If this model is correct, KP metabolites could serve to predict who is likely to develop psychiatric illness while drugs that target the KP could help to prevent or treat depression and anxiety arising in the context of TBI.